4-(O,O-Diester phosphoryloxy)cyclohex-4-en-1,2-carboxylic anhydrides

ABSTRACT

Dienylphosphates of the formula ##STR1## wherein each of R 1  and R 1  &#39; is lower alkyl, aryl or benzyl and each of R 2 , R 3  and R 4  is hydrogen or lower alkyl, 
     Are useful as anthelmintic agents and as intermediates for enolphosphates having anthelmintic activity.

This is a division of application Ser. No. 618,853 filed Oct. 2, 1975,now U.S. Pat. No. 4,025,584, which in turn is a division of applicationSer. No. 497,598, filed Aug. 15, 1974, now U.S. Pat. No. 3,933,948,granted Jan. 20, 1976.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a series of compounds, referred to asdienylphosphates, represented by the formula ##STR2## wherein each of R₁and R₁ ' is lower alkyl, aryl or benzyl and each of R₂, R₃ and R₄ ishydrogen or lower alkyl.

As used herein, the term "lower alkyl" refers to a monovalentsubstituent consisting solely of carbon and hydrogen having a straightchain of from 1 to 5 carbon atoms. The term "aryl" refers to phenyl orphenyl substituted with one or more lower alkyl, halo (fluorine,chlorine or bromine), nitro or lower alkoxy (lower alkyl linked throughan ether oxygen) groups.

Depiction of dienes in the s-cis conformation is for convenience only,and does not necessarily represent the actual geometrical conformationat any particular time.

Preferred compounds falling within the above genus are those where R₁and R₁ ' are methyl or ethyl and R₂, R₃ and R₄ are hydrogen. Thus,particularly preferred compounds of the present invention are dimethyl(1,3-butadien-2-yl) phosphate [alternate nomenclature - dimethyl1-vinylvinylphosphate]; and diethyl (1,3-butadien-2-yl) phosphate[alternate nomenclature-diethyl 1-vinylvinylphosphate].

Compounds of formula I may be prepared from readily available startingmaterials by simple chemical procedures.

Compounds of formula I where R₂, R₃ and R₄ are hydrogen and where R₁ andR₁ ' are identical are prepared from 3,4-dichlorobutanone by reactionwith a phosphite of the formula

    P(OR.sub.1).sub.3                                          II

wherein R₁ is as above.

Representative phosphites include trimethylphosphite, triethylphosphite,tri(n-propyl)phosphite, tri-(n-butyl)-phosphite, tri(n-pentyl)phosphite,triphenylphosphite and tribenzylphosphite. Particularly preferredphosphites are trimethylphosphite and triethylphosphite.

The reaction is conveniently preformed in the absence of solvents otherthan the reactants. However, if desired, inert organic solvents may beemployed. Suitable inert organic solvents include, for example,hydrocarbons such as hexane, benzene and toluene; halogenatedhydrocarbons such as dichloromethane, and the like.

The reaction appears to occur in two stages. The first stage occursreadily at temperatures from about 0° to about 50° C, preferably about20° to 30° C, with the evolution of an alkyl chloride, R₁ Cl. The finalstage of the reaction involves the elimination of hydrogen chloride.This occurs by heating at a temperature of from about 50° to about 150°C, and is most conveniently carried out by distillation of the reactionmixture, preferably under reduced pressure. There is thus obtained thefinal product of formula I wherein R₂, R₃ and R₄ are each hydrogen.

To enhance the elimination of the hydrogen chloride during thedistillation step, it is preferable to add a small quuantity (forexample, less than 1 mole %) of a Lewis acid such as aluminum chloride.To prevent polymerization of the diene of formula I during distillation,the addition of a small quantity (for example, 1 mole % or less) of apolymerization inhibitor such as hydroquinone is preferred.

The preparation of dienylphosphates from 3,4-dichlorobutanone andphosphites is indeed unexpected, since the identical reaction utilizing3,4-dibromobutanone is known to afford exclusively methyl vinyl ketone,J. P. Schroeder, et al., J. Org. Chem. 35, 3181 (1970).

The full scope of compounds of formula I may be prepared by a differentprocedure, starting with a conjugated ketone of the formula ##STR3##wherein R₂, R₃ and R₄ are as above.

This procedure involves, first, the conversion of the compound offormula III to its enolate of the formula ##STR4## wherein R₂, R₃ and R₄are as above and M⁺ is the cation of sodium, potassium or lithium.

Conversion of the compound of formula III to its enolate is carried outby reaction of the ketone with a strong organic soluble alkali metalamide base in an inert organic solvent at a low temperature. Preferredbases are alkali metal alkyl or cycloalkyl amides such as ligthiumN-cyclohexyl N-isopropylamide, lithium cyclohexylamide; and alkali metalsilylamides, such as sodium bis(trimethylsilyl)amide. The amide basesutilized in the present process amy be prepared by methods well known inthe art.

Suitable inert organic solvents for the present reaction include, forexample, organic ethers, e.g., diethyl ether, dioxane andtetrahydrofuran; hydrocarbons such as hexane and heptane; and so forth.

The enolate, prepared in situ as hereinabove described, is then reactedwith a halophosphate of the formula ##STR5## wherein R₁ and R₁ ' are asabove and Y is chlorine, bromine or iodine.

Both the formation of the enolate and the subsequent reaction with thehalophosphate may be suitably conducted at a reduced temperature, forexample, from about -80° to about -20° C. A particularly preferredtemperature range from about -65° to about -75° C.

After standard workup conditions, the product of formula I is isolatedand purified. A particularly preferred purification method involvesdistillation at reduced pressure. Among the compounds of formula I thatmay be prepared by this method there may be mentioned:

dimethyl (1,3-butadien-2-yl) phosphate

diethyl (1,3-butadien-2-yl) phosphate

dimethyl (1,3-pentadien-3-yl) phosphate

diethyl (1,3-pentadien-3-yl) phosphate

dimethyl (1,3-pentadien-2-yl) phosphate

diethyl (1,3-pentadien-2-yl) phosphate

dimethyl (3-methyl-1,3-butadien-2-yl) phosphate

diethyl (3-methyl-1,3-butadien-2-yl) phosphate

dimethyl (3-methyl-1,3-pentadien-2-yl) phosphate

diethyl (3-methyl-1,3-pentadien-2-yl) phosphate

dimethyl (2-methyl-1,3-pentadien-3-yl) phosphate

diethyl (2-methyl-1,3-pentadien-3-yl) phosphate

dimethyl (3-ethyl-1,3-hexadien-2-yl) phosphate

diethyl (3-ethyl-1,3-hexadien-2-yl) phosphate

dimethyl (2-ethyl-1,3-hexadien-3-yl) phosphate

diethyl (2-ethyl-1,3-hexadien-3-yl) phosphate

dimethyl (4-methyl-3,5-decadien-5-yl) phosphate

diethyl (5-ethyl-3,5-nonadien-4-yl) phosphate

dimethyl (4-methyl-2,4-decadien-3-yl) phosphate

diethyl (4-propyl-3,5-nonadien-5-yl) phosphate

The compounds of formula I are substituted dienes and are highlyreactive towards dienophiles in Diels-Alder reactions to form1,4-cycloadducts (enolphosphates) of the formula ##STR6## wherein R₁, R₁', R₂, R₃ and R₄ are as above and Z is the residue of a dienophilemoiety.

For the purposes of this specification, a dienophile is defined as anunsaturated organic compound which will take part in a 1,4-cycloadditionreaction with a conjugated diene. Most dienophiles have a nonaromaticunsaturated (double or triple bond) linkage upon which there is directlysubstituted at least one electron withdrawing group. Among the types ofdienophiles which may be mentioned are: nitriles, e.g.,tetracycanoethylene and acrylonitrile; aldehydes, e.g., crotonaldehydeand acrolein; acids, e.g., acrylic acid, cinnamic acid, maleic acid andfumaric acid; esters, e.g., ethyl acrylate, dimethyl maleate, dimethylfumarate, diethyl acetylenedicarboxylate, diethylazodicarboxylate;anhydrides, e.g., maleic anhydride and citraconic anhydride; imides,e.g., N-phenylmaleimide, 4-phenyl-1,2,4-triazoline-3,5-dione andp-phenylazomaleinanil; nitroso compounds, e.g., nitrosobenzene, nitrocompounds, e.g., β-nitrostyrene and 1-nitropropene; ketones, e.g.,methyl vinyl ketone; and so forth.

Preparation of Diels-Alder adducts from compounds of formula I iscarried out according to the usual methods well known in the art forsuch reactions. Thus, the Diels-Alder reaction is conveniently performedby admixture of a diene (the compound of formula I) with a dienophile.

The reaction may be carried out in the absence of any solvent, or aninert organic solvent may be utilized. Suitable inert organic solventsthat may be mentioned include, for example, hydrocarbons such as hexane,heptane, benzene and toluene; halogenated hydrocarbons, such asdichloromethane; organic ethers, such as diethyl ether, tetrahydrofuranand dioxane; and the like. The Diels-Alder reaction may be carried outover a wide range of temperature conditions from about 0° to about +150°C. A preferred temperature range is from about 20° to about 70° C.

The dienylphosphates of formula I are useful as anthelmintic agents.Furthermore, the enolphosphates of formula V also have anthelminticproperties. Thus, the compounds of formula I are additionally valuableas intermediates for the preparation of compounds of formula V.

Specifically, these compounds are effective, upon oral administration(0.1% in feed) in the control of Ascaris suum infection in mice.

Compounds of formula I, as has been demonstrated hereinabove, are alsouseful as reagents in organic synthesis as diene moieties for use inDiels-Alder reactions for the construction of more complex organicmolecules.

Additionally, dienes of formula I serve as valuable monomers which maybe either self-polymerized, or co-polymerized with monomers well knownin the art, to prepare complex polymeric structures having a variety ofuseful properties, for example as flame retardants.

The preparation of compounds of formula I and V, as well as processestherefor, are illustrated by the following specific examples. Theseexamples are illustrative only of the invention and are not to beconstrued as limitative thereof in any manner.

EXAMPLE 1 3,4-Dichlorobutanone

Chlorine was introduced into a solution of 140 g (1 mole) of methylvinyl ketone in 600 ml of chloroform with ice-cooling. When 142 g ofchlorine (1 mole) had been absorbed, the chloroform was evaporated (bathtemperature <35°) leaving 290 g of slightly impure 3,4-dichlorobutanonewhich was used without further purification.

EXAMPLE 2 Diethyl 1-vinylvinylphosphate hemihydrate

Triethyl phosphite (166 g, 1 mole) was cooled in an ice bath and3,4-dichlorobutanone (140 g, 1 mole) was added. The mixture was stirredunder nitrogen atmosphere for 2 hr at 0° then for 20 hr at roomtemperature. After 0.5 g of hydroquinone and 0.5 g of aluminum chloridehad been added, the mixture was distilled in vacuo to give 34.4 g ofpure diethyl 1-vinylvinylphosphate hemihydrate, b.p. 91°-92°/2 mm.

Anal. Calcd for C₈ H₈ PO₄.1/2 H₂ O (215.19): C, 44.75; H, 7.49; Found :C, 45.14; H, 7.40.

EXAMPLE 3 Dimethyl 1-vinylvinylphosphate

Trimethyl phosphite (28.6 g) was treated with 3,4-dichlorobutanone (32g) using the identical procedure as in Example 2. Distillation gave puredimethyl 1-vinylvinylphosphate, bp 79°-83°/1.5 mm.

Anal. Calcd. for C₆ H₁₁ PO₄ (178.13): C, 40.46; H, 6.23; Found : C,39.83; H, 6.25.

UV 220 nm (ε 16520) in methanol.

EXAMPLE 4 1,1,2,2-Tetracyano-4-(O,O-diethylphosphoryloxy)cyclohex-4-ene

To a solution of 2.15 g (0.01 mole) of diethyl 1-vinylvinylphosphate in10 ml of tetrahydrofuran was added under a nitrogen atmosphere 1.28 g(0.01 mole) of tetracyanoethylene. The yellow solution was left standingat room temperature for 2 days before it was evaporated. The residualsyrup was taken up in ethyl acetate. Petroleum ether was added toincipient turbidity and the mixture was stored at 0° for 5 days.Filtration gave 2.10 g of1,1,2,2-tetracyano-4-(O,O-diethylphosphoryloxy)cyclohex-4-ene, mp97°-98°. Recrystallization from ethyl acetate-petroleum ether affordedlong prisms and short plates of pure material both having m.p. 98°.

Anal. Calcd for C₁₄ H₁₄ N₄ O₄ P (333.27): C, 50.46; H, 4.23; N, 16.81;Found : C, 50.61; H, 4.54; N, 16.98.

IR (Nujol mull): νmax 1665, 1260 and 1045 cm⁻¹.

NMR (CDCl₃), τ: 8.61 (triplet, 6H); 6.69 (multiplet, 4H); 5.75 (quintet,4H), 4.12 (multiplet, 1H).

EXAMPLE 5 4-(O,O-dimethylphosphoryloxy)-cyclohex-4-en-cis-1,2-carboxylicanhydride

A mixture of 0.98 g (0.01 mole) of maleic anhydride and 1.78 g (0.01mole) of dimethyl 1-vinylvinylphosphate in 50 ml of benzene was stirredat room temperature for 20 hr. Evaporation gave a syrup whichcrystallized from ethyl acetate-petroleum ether to give 0.810 g of 4(O,O-dimethylphosphoryloxy)-cyclohex-4-en-cis-1,2-carboxylic anhydride,mp 71°-72°. Recrystallization from the same solvent system gave prisms,mp 73°-74°.

Anal. Calcd for C₁₀ H₁₃ O₇ P (276.18): C, 43.49; H, 4.74; Found: C,43.44; H, 4.71.

IR (Nujol mull): 1850, 1785, 1670, 1275 and 1045 cm⁻¹.

EXAMPLE 62-Phenyl-4(O,O-diethylphosphoryloxy)-3,6-dihydro-2H-1,2-oxazine

To a solution of 3.24 g (0.03 mole) of nitrosobenzene in 150 ml ofmethylene chloride was added 6.25 g (0.029 mole) of diethyl1-vinylvinylphosphate. The mixture was left standing at room temperaturefor 20 hr before it was evaporated. The remaining crude product waspurified on a silica gel column and eluted with ethyl acetate-petroleumether, 1:2 to give 7.1 g of slightly colored2-phenyl-4(O,O-diethylphosphoryloxy)-3,6-dihydro-2H-1,2-oxazine.

Anal. Calcd for C₁₄ H₂₀ NO₅ P (313.30): C, 53.67; H, 6.43; N, 4.47;Found : C, 53.52; H, 6.57; N, 4.26.

UV (ethanol); 240 (ε 7880), 282 nm (ε 850).

NMR (CDCl₃), τ: 6.15 (s), 5.50 (m), 4.25 (m).

EXAMPLE 7 1-Acetyl-3-(O,O-dimethylphosphoryloxy)cyclohex-3-ene and1-acetyl-4-(O,O-dimethylphosphoryloxy)cyclohex-3-ene

Dimethyl 1-vinylvinylphosphate (1.78 g) was dissolved in 30 ml of methylvinyl ketone and stirred for 20 hr at 65° under an atmosphere ofnitrogen. The excess methyl vinyl ketone was evaporated off to give 3.60g of crude product which was purified by column chromatography.

Anal. Calcd for C₁₀ H₁₇ PO₅ (248.22): C, 48.39; H, 6.91; Found : C,48.58; H, 7.00.

The position of the acetyl peaks in the NMR spectrum indicated that theproduct was a mixture of isomers.

EXAMPLE 8 Preparation of2-phenyl-6(O,O-diethylphosphoryloxy)-2,3,5,8-tetrahydro-1H-s-triazolo[1,2a]pyridazine-1,3-dione

A benzene solution of equivalent amounts ofdiethyl-1-vinylvinylphosphate and 4-phenyl-1,2,4-triazoline-3,5-dione isallowed to stand at room temperature for 10-20 hrs. The solvent isseparated, and the residue is crystallized from benzene-hexane to givecolorless crystals of product, m.p. 84°-85°.

Anal. Calcd. for C₁₆ H₂₀ H₃ O₆ P (381.33): C, 50.40; H, 5.29; N, 11.01;P, 8.12; Found: C, 50.58; H, 5.27; N, 11.14; P, 8.10.

EXAMPLE 9 Preparation of diethyl 1-vinylvinylphosphate from methyl vinylketone

A solution of 31 g (0.22 moles) of N-cyclohexyl N-isopropylamine in 400ml of tetrahydrofuran is cooled to -70°. To the stirred solution, 0.22moles of n-butyllithium in hexane are added dropwise over a 5 min.period, followed by 14 g (0.20 moles) of methyl vinyl ketone during a 20min. period, followed by 37.8 g (0.22 moles) of diethyl chlorophosphateduring a 10 min. period. After an additional 90 min. at -70°, thesolution is allowed to warm to room temperature. It is diluted withmethylene chloride, and then washed sequentially with 5% aqueous NaHCO₃,1 N aqueous HCl, and 10% aqueous NaCl solution. The organic phase isdried and evaported, and the residue distilled to yield 22-25 g diethyl1-vinylvinylphosphate, b.p. 74°/0.5 mm.

We claim:
 1. A compound of the formula ##STR7## wherein each of R₁ andR₁ ' is lower alkyl, phenyl, phenyl substituted by one or more loweralkyl, fluorine, chlorine, bromine, nitro and lower alkoxy or benzyl,each of R₂, R₃ and R₄ is hydrogen or lower alkyl and Z is the residue ofa dienophile moiety selected from the group consisting of maleicanhydride and citraconic anhydride.
 2. The compound of claim 1 whereinR₁ is methyl or ethyl.
 3. The compound of claim 1 wherein each of R₂, R₃and R₄ is hydrogen.
 4. The compound of claim 3 which is4(O,O-dimethylphosphoryloxy)-cyclohex-4-en-cis-1,2-carboxylic anhydride.